Liver X receptors orchestrate osteoblast/osteoclast crosstalk and counteract pathologic bone loss

Kleyer, Arnd; Scholtysek, Carina; Bottesch, Edith; Hillienhof, Ulrike; Beyer, Christian; Distler, Jörg H W; Tuckermann, Jan; Schett, Georg; Krönke, Gerhard

doi:10.1002/jbmr.1702

Cited by 36 publications

(41 citation statements)

References 23 publications

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“…Modulation of inflammatory signaling by LXRs substantiates its use as a therapeutic target for inflammatory diseases. With respect to pathological bone disease, activation of LXRs has been demonstrated to play a protective role in the prevention of rheumatoid arthritis [30], osteoarthritis [31], [32], and postmenopausal osteoporosis [33]. In the past years, there have been several experiments focusing on the association between LXRA and/or LXRB gene polymorphisms with different diseases.…”

Section: Discussionmentioning

confidence: 99%

Liver X Receptor Gene Polymorphisms in Tuberculosis: Effect on Susceptibility

Han

Liu

et al. 2014

PLoS ONE

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ObjectivesThe Liver X receptors (LXRs), Liver X receptor A (LXRA) and Liver X receptor B (LXRB), regulate lipid metabolism and antimicrobial response. LXRs have a crucial role in the control of Mycobacterium tuberculosis (M.tb). Lacking LXRs mice is more susceptibility to infection M.tb, developing higher bacterial burdens and an increase in the size and number of granulomatous lesions. We aimed to assess the associations between single nucleotide polymorphisms (SNPs) in LXRs and risk of tuberculosis.MethodsWe sequenced the LXRs genes to detect SNPs and to examine genotypic frequencies in 600 patients and 620 healthy controls to investigate for associations with tuberculosis (TB) in the Chinese Han population. DNA re-sequencing revealed eight common variants in the LXRs genes.ResultsThe G allele of rs1449627 and the T allele of rs1405655 demonstrated an increased risk of developing TB (p<0.001, p = 0.002), and the T allele of rs3758673, the T allele of rs2279238, and the C allele of rs1449626 in LXRA and the C allele of rs17373080, the G allele of rs2248949, and the C allele of rs1052677 in LXRB were protective against TB patients compared to healthy controls (p = 0.0002, p = 0.006, p<0.001, p = 0.004, p = 0.008, p = 0.003, respectively). All SNP genotypes were significantly associated with TB. An estimation of the frequencies of haplotypes revealed two potential risk haplotypes,GGCG in LXRB (p = 0.004,) and TTCG in LXRA (p<0.001, p = 0.004). Moreover, three protective haplotypes, TTAT and CCAT in LXRA and CATC in LXRB, were significantly “protective” (p = 0.008, p<0.001, p = 0.031) for TB. Furthermore, we determined that the LXRs SNPs were nominally associated with the clinical pattern of disease.ConclusionsOur study data supported that LXRs play a fundamental role in the genetic susceptibility to TB and to different clinical patterns of disease. Thus, further investigation is required in larger populations and in additional areas.

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Section: Discussionmentioning

confidence: 99%

Liver X Receptor Gene Polymorphisms in Tuberculosis: Effect on Susceptibility

Han

Liu

et al. 2014

PLoS ONE

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“…Since full activation of the SREBP1 promoter requires participation by LXR, we speculate that bone osteocytes secrete a lipid-like activator of LXR. 46,66 Osteocytes are known to produce oxysterols which could bind to and activate the LXR receptor. Alternatively, as noted above, PPAR-g receptor regulates several aspects of muscle regeneration following exercise.…”

Section: Dec1 and Dec2 Are Subject To Regulation By Circadian Core Prmentioning

confidence: 99%

Bone muscle crosstalk targets muscle regeneration pathway regulated by core circadian transcriptional repressors DEC1 and DEC2

Gorski

Price

2016

BoneKEy Reports

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Deletion of proprotein convertase Mbtps1 in bone osteocytes leads to a significant postnatal increase in skeletal muscle size and contractile function, while causing only a 25% increase in stiffness in long bones. Concerns about leakiness in skeletal muscle were discounted since Cre recombinase expression does not account for our findings, and, Mbtps1 protein and mRNA is not deleted. Interestingly, the response of normal skeletal muscle to exercise and the regenerative response of skeletal muscle to the deletion of Mbtps1 in bone share some key regulatory features including a preference for slow twitch muscle fibers. In addition, transcriptional regulators PPAR, PGC-1a, LXR, and repressors DEC1 and DEC2 all occupy central positions within these two pathways. We hypothesize that the age-dependent muscle phenotype in Dmp1-Cre Mbtps1 cKO mice is due to bone-muscle crosstalk. Many of the myogenic genes altered in this larger and functionally improved muscle are regulated by circadian core transcriptional repressors DEC1 and DEC2, and furthermore, display a temporal coordination with Dec1 and Dec2 expression consistent with a regulatory co-dependency. These considerations lead us to propose that Dmp1-Cre Mbtps1 cKO osteocytes activate myogenesis by increased release of an activator of muscle PPAR-gamma, for example, PGE 2 or sphingosine-1-P, or, by diminished release of an inhibitor of LXR, for example, long-chain polyunsaturated fatty acids. We hope that further investigation of these interacting pathways in the Dmp1-Cre Mbtps1 cKO model will lead to clinically translatable findings applicable to age-related sarcopenia and other muscle wasting syndromes.

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“…Remen et al (108) show that LXR activation by GW3965 significantly inhibits osteoclast differentiation and bone resorption in an LXR␤-dependent manner, potentially via suppressing the NFATc1/p38/microophthalmia-associated transcription factor axis. Kleyer et al (109) show that LXR agonists can protect female mice from OVX-induced bone loss by decreasing the RANKL to OPG ratio. Similarly, two reports in 2013 show that LXR agonists can attenuate lipopolysaccharide-induced osteoclast differentiation by suppressing the activity of NFB and c-fos to reduce the expression of osteoclast markers Acp5, Ctsk, Mmp-9, dendritic cell-specific transmembrane protein, and Itg␤3 (110,111).…”

Section: Liver X Receptor (Lxr)mentioning

confidence: 99%

Minireview: Nuclear Receptor Regulation of Osteoclast and Bone Remodeling

Jin

Wan

2015

Molecular Endocrinology

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Osteoclasts are bone-resorbing cells essential for skeletal remodeling and regeneration. However, excessive osteoclasts often contribute to prevalent bone degenerative diseases such as osteoporosis, arthritis, and cancer bone metastasis. Osteoclast dysregulation is also associated with rare disorders such as osteopetrosis, pycnodysostosis, Paget's disease, and Gorham-Stout syndrome. The nuclear receptor (NR) family of transcription factors functions as metabolic sensors that control a variety of physiological processes including skeletal homeostasis and serves as attractive therapeutic targets for many diseases. In this review, we highlight recent findings on the new players and the new mechanisms for how NRs regulate osteoclast differentiation and bone resorption. An enhanced understanding of NR functions in osteoclastogenesis will facilitate the development of not only novel osteoprotective medicine but also prudent strategies to minimize the adverse skeletal effects of certain NR-targeting drugs for a better treatment of cancer and metabolic diseases.

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Liver X receptors orchestrate osteoblast/osteoclast crosstalk and counteract pathologic bone loss

Cited by 36 publications

References 23 publications

Liver X Receptor Gene Polymorphisms in Tuberculosis: Effect on Susceptibility

Liver X Receptor Gene Polymorphisms in Tuberculosis: Effect on Susceptibility

Bone muscle crosstalk targets muscle regeneration pathway regulated by core circadian transcriptional repressors DEC1 and DEC2

Minireview: Nuclear Receptor Regulation of Osteoclast and Bone Remodeling

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